Phosphodiesterase (PDE) catalyzes the hydrolization of cyclic nucleotides cGMP and cAMP, and regulates various physiological responses by controlling the intramolecular concentrations of these two important second messengers. The abnormal intramolecular regulation of the cyclic nucleotides cGMP and cAMP is the cause of many diseases, there are already a number of drugs that can improve and treat diseases by inhibiting the PDE activity, such as PDE5 inhibitors for pulmonary hypertension and PDE4 inhibitors for arthritis caused by psoriasis. There are eleven categories of the currently known phosphodiesterase genes, each category can be expressed in several subtypes, with a total of more than 100 PDE subtypes. Different subtypes have different structure and different tissue distribution, the activity of cyclic nucleotides cGMP and cAMP and the physiological function of regulation are also very different.
PDE2 phosphodiesterase can catalyze the hydrolization of cyclic nucleotides cGMP and cAMP, meanwhile cAMP activity is regulated by cGMP, which plays a key role in intracellular balance of cGMP and cAMP function. PDE2 is widely expressed in human tissues, mainly distributed in the heart, central nervous system, liver, adrenal gland, endothelial cells, and platelets and so on. PDE2 is involved in regulating various physiological activities, such as learning, memory and cognitive processes of the maincenter, the maintenance of the basic rhythm of the heart, smooth muscle and endothelial cells, the maintenance of the permeability of endothelial cells, the regulation of inflammatory response. The knockout of the PDE2 gene will lead to the death of mouse embryos. Inhibition of PDE2 activity may be used for a variety of maincenter diseases, cardiovascular diseases, and controlling inflammation.
The non-selective PDE inhibitory activity of a variety of natural and synthetic purine compounds has been found very early, such as caffeine, theophylline, pentoxifylline and so on. Pentoxifylline (PDE2 activity) has been approved for clinical use in lower limbs claudication caused by peripheral vascular occlusion, the main functions of which are reducing blood viscosity, improving erythrocyte deformation, inhibiting platelet aggregation, etc. Novel high-selectivitive PDE2 inhibitors have also been reported to control the division of endothelial cells and the regeneration of blood vessels, and to improve maincenter disgnosia. However, overall, the development and application of novel selectivitive PDE2 inhibitors are still very limited, and the discovery and application of novel PDE2 inhibitors has broad prospects.
Tumor necrosis factor alpha (TNFα) is a cytokine with multiple biological activities, which has a significant impact on the occurrence, development and prognosis of multiple diseases. TNFα is mainly produced by monocytes and macrophage cells, which is involved in the immunomodulation and the cytokine network coordination. Under normal circumstances, TNFα plays an important role in immune defense and immune surveillance, but in some cases it has adverse effects. Research shows that the overexpression of TNFα can induce the expression of proinflammatory cytokines such as interleukin 1 (IL-1) and IL-6, increase the permeability of endothelial cells and up-regulate the expression of adhesion molecules and activate neutrophils and eosinophils, and induce bone synovial cells and cartilage cells to secrete acute phase substances and tissue-degrading enzymes and the like to promote the occurrence of inflammation. These pathologic reactions play a very important role in occurrence and development of many immune-mediated inflammatory diseases (IMID), such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), inflammatory bowel disease (IBD), juvenile chronic arthritis (JCA) and vasculitis, etc. Studies have shown that TNFα is an ideal target for above multiple IMIDs, and the use of TNFα antagonists (TNFα inhibitors) to neutralize excess TNFα is an ideal way to effectively prevent chronic inflammatory diseases due to TNFα overexpression. PDE2 regulates the expression of TNFα according to the mechanism, therefor the level of TNFα can be controlled by regulating the PDE2 activity, so as to control the inflammation.